Cross-flow filtration (also referred to as diafiltration) technology has been used widely in industry globally and is largely applied to process aqueous feed streams. When purifying water, it can be very cost effective in comparison to the traditional evaporation methods. The a-thermal solvent exchange in solutions from one organic synthesis step to the next step in pharmaceutical manufacturing by diafiltration using organic solvent resistant membranes has been suggested (Sheth J. P., et al, Journal of Membrane Science 211 (2003), 251-261.
However the use of cross flow filtration technology for liquid medium exchange between pharmaceutical suspensions in the working-up of the drug from its synthesis so as to obtain the drug in particulate form, or in the direct production of a drug product comprising the drug, wherein the step of first isolating particles can be bypassed has been not described before.
In pharmaceutical suspensions it is generally desired to provide the drug in the form of particles, particularly crystalline particles, of a relatively small size, and of a desired size distribution. The drug particles are ultimately formulated into a drug product, in the form of a suspension of said particles.
The formation of the desired particle sizes and the desire of obtaining a stable suspension in a pharmaceutically acceptable liquid medium, presents several technical challenges. One is that obtaining particles, notably crystalline particles, requires precipitation from a solution or suspension in a controlled way. To this end, e.g. in the case of cefquinome sulfate, acetone is added to water, or to a mixture of water and acetone, so as to force precipitation. This brings about a relatively high volume of solvent (or, rather, the anti-solvent acetone), which moves the production of commercially viable batch sizes in an uneconomical direction.
It would therefore be desired to provide a method by which particles, notably crystalline particles, of the desired particle size can be obtained on the basis of a substantially reduced volume of anti-solvent.
It would also be desired to provide a method by which the particles agglomerates to bigger particle collective to ease the filtration step if the particles should be separated as such.
Further, in the existing processes, the final drug product is a suspension, in a pharmaceutically acceptable liquid medium such as ethyl oleate, of the crystalline particles as produced in the desired particle size at an earlier stage of the process. The overall process therefore requires not only the controlled precipitation of the particles, but also isolation, drying, packaging, transportation, and formulation. It would be desired to be able to dispense with one or more of the steps in between the formation of the particles (viz. in a suspension) and the production of the final formulation (also a suspension).